Signal transducer and activator of transcription 3 (“STAT3”) is a member of the STAT family of transcription factors that relate signals from extracellular signaling protein receptors on the plasma membrane directly to the nucleus. See e.g., Bromberg, J., et al., The Role of STATs in Transcriptional Control and their Impact on Cellular Function, Oncogene, 19, 2468-2473 (2000).
STAT3 has been shown to be constitutively activated in cancer including, but not limited to, cancers of the brain, head, neck, breast, prostate, lung, ovary, pancreas, leukemia, multiple myeloma, and lymphoma. See e.g., Song, J. I., et al., STAT Signaling in Head and Neck Cancer, Oncogene, 19, 2489-2495 (2000); Garcia, R., et al., Constitutive Activation of STAT3 in Fibroblasts Transformed By Diverse Oncoproteins and in Breast Carcinoma Cells, Cell Growth Duff., 812, 1267-76 (1997); Schaefer, L. K., et al., Constitutive Activation of STAT3 in Brain Tumors: Localization to Tumor Endothelial Cells and Activation by the Endothelial Tyrosine Kinase Receptor (VEGFR-2), Oncogene, 21, 2058-2065 (2002); Dhir, R., et al., STAT3 Activation in Prostatic Carcinomas, Prostate, 51, 241-246 (2002); Seki Y.; et al., STAT3 and MAPK in Human Lung Cancer Tissues and Suppression Of Oncogenic Growth by JAB and Dominant Negative STAT3, Int. J. Oncology, 24, 931-934 (2004); Huang, M., et al., Constitutive Activation of STAT3 Oncogene Product in Human Ovarian Carcinoma Cells, Gynecol. Oncol., 79, 67-73 (2000); Scholz, A., et al., Activated Signal Transducer and Activator of Transcription 3 (STAT3) Supports the Malignant Phenotype of Human Pancreatic Cancer, Gastroenterology, 125, 891-905 (2003); Benekti, M., et al., Signal Transducer and Activator of Transcription Proteins in Leukemias,Blood, 101, 2940-2954 (2003); Weber-Nordt, R. M., et al., Constitutive Activation of STAT Proteins in Primary Lymphoid and Myeloid Leukemia Cells and in Epstein-Barr Virus (EBV)-Related Lymphoma Cell Lines, Blood, 88, 809-816 (1996a); Bowman, T., et al., STATs In Oncogenesis, Oncogene, 19, 2474-2488 (2000); Yu, H.; Jove, R. The STATs of cancer—new molecular targets come of age. Nat Rev Cancer 4, 97-105, (2004).
Certain small molecules have been designed to inhibit STAT3, but are poor inhibitors of STAT3 because the molecule is either not selective and/or have low affinity for binding, or low potency as a potential drug product. For example, small molecules have been designed around a portion of the STAT3 molecule but have reported a low binding affinity. Dourlate et al 2007. Similarly, several small molecules have been reported to inhibit Stat3 phosphorylation in cells but they are not selective for Stat3 and impact other pathways and processes in cells. For example, cryptotanshinone, a known COX-2 inhibitor, was recently reported to inhibit STAT3 activity in tumor cells. D. S.; Kim, et al., Cryptotanshinone Inhibits Constitutive Signal Transducer And Activator Of Transcription 3 Function Through Blocking The Dimerization In DU145 Prostate Cancer Cells, Cancer Res, 69, 193-202 (2009). According to the reported model, it binds to the phosphotyrosine site on STAT3. While cryptotanshinone inhibits NF-kB inhibition and activation of the PI3K/Akt pathway, it is it is unlikely that cryptotanshinone binds to the SH2 domain of STAT3 in cultured cells.
Another example of a compound that reportedly inhibits constitutive phosphorylation of STAT3 and is potentially useful to treat hematopoietic malignancies is CDDO-Me. Ahmad, R., et al., Triterpenoid CDDO-Methyl Ester Inhibits the Janus-Activated Kinase-1 (JAK1)→Signal Transducer and Activator of Transcription-3 (STAT3) Pathway By Direct Inhibition Of JAK1 And STAT3, Cancer Res, 68, 2920-6 (2008); Ling, X., et al., The Novel Triterpenoid C-28 Methyl Ester of 2-Cyano-3,12-Dioxoolen-1,9-Dien-28-Oic Acid Inhibits Metastatic Murine Breast Tumor Growth Through Inactivation Of STAT3 Signaling, Cancer Res, 67, 4210-8 (2007). However, this compound also inhibits NF-κB, and targets mitochondrial glutathione Ahmad, R., et al., D. Triterpenoid Cddo-Me Blocks the NF-Kappab Pathway by Direct Inhibition of Ikkbeta on Cys-179, J Biol Chem, 281, 35764-9 (2006); Samudio, I. et al, 2-Cyano-3,12-dioxooleana-1,9-dien-28-imidazolide (CDDO-Im) Directly Targets Mitochondrial Glutathione To Induce Apoptosis In Pancreatic Cancer, J Biol Chem, 280, 36273-82 (2005). It also induces apoptosis by interfering with the redox potential of the cell. Ikeda, T., et al, The Novel Triterpenoid CDDO and its Derivatives Induce Apoptosis by Disruption of Intracellular Redox Balance Cancer Res, 63, 5551-8 (2008). In short, the compound is not a selective inhibitor of STAT3 activation or phosphorylation.
A need exists therefore for selective, potent STAT3 inhibitors useful in treating cancer and other STAT3-mediated diseases.